PROJECT SUMMARY Breast cancer growth and progression require complex interactions between tumor cells and their surrounding environment. Understanding the key tumor-stromal interactions that drive breast cancer growth and metastasis is critical for the development of strategies to inhibit tumor progression and recurrence. Breast cancers are often associated with an inflammatory environment, which has been linked to enhanced breast cancer progression. The availability of anti-inflammatory agents for clinical use enhances the feasibility of targeting the inflammatory microenvironment. However, understanding the mechanisms that drive the formation of an inflammatory environment and identifying key mediators that contribute to breast cancer growth and progression are critical for developing successful anti-inflammatory therapeutic strategies. Fibroblast growth factors (FGFs) are well-established promoters of cancer growth and progression. Collectively, FGFs and their receptors (FGFRs) are overexpressed and/or amplified in up to 75% of human breast cancers and increased FGFR activity is correlated with poor patient outcome. We have recently found that FGFR activation leads to pro-tumorigenic alterations within the extracellular matrix (ECM) including enhanced synthesis and fragmentation of the ECM component hyaluronan. Furthermore, we have identified a novel pathway activated by hyaluronan in breast cancer cells along with pro-inflammatory mediators that contribute to hyaluronan function. These studies have led to the hypothesis that activation of FGFR in breast cancer cells leads to the formation of an HA-rich inflammatory microenvironment, which promotes tumor growth and progression by activating pro-inflammatory signaling pathways and promoting expression of inflammatory mediators. The following specific aims are proposed: 1) Determine the functional contributions of FGFR-mediated HA synthesis and fragmentation to mammary tumor progression. 2) Delineate the specific signaling pathway through which HA regulates inflammatory gene expression in breast cancer cells. 3) Develop combination therapies that target FGFR and downstream HA effectors. The significance of these studies is that they will define novel interactions between tumor cells and the ECM. A major goal of these studies is to determine the ability of combination therapies that target both tumor cells and HA: receptor interactions in the microenvironment to limit tumor initiation and growth.